The objective of this project is to investigate molecular mechanisms of synaptic damage and plasticity after transient cerebral ischemia (TCI). TCI selectively causes delayed neuronal death and leads to neurological deficits. Neurological functional recovery after stroke, which requires precise cell-to-cell communication through synapses, is a key issue for stroke patients. Therefore, studies of morphological and molecular alterations of synapses are relevant to understanding the mechanisms of ischemic neuronal loss and neurological outcome. However, very few studies on changes in synapses after ischemia have been conducted. We have recently established a series of techniques to study synaptic changes after brain insults, and found dramatic ultrastructural and biochemical alterations of synapses after TCI. The focus of the present proposal is to extend our previous studies and to propose new studies on synaptic remodeling after TCI. We will test a general hypothesis that progressive synaptic damage develops due both to damage induced by the ischemic event and to the lack of synaptic repair mediated by the ERK-CREB signaling cascade in ischemically vulnerable neurons after transient cerebral ischemia. The specific aims are: 1. To study the synaptic alterations in multiple brain regions after various ischemic durations. 2. To investigate molecular reorganization of synapses after ischemia. 3. To study the regulatory role of the ERK-CREB cascade in synaptic remodeling after ischemia. Synaptic transmission is a very plastic process that is regulated via morphological changes, biochemical modification and molecular remodeling. Severe brain insults can damage synapses and induce neurological dysfunction. Understanding synaptic plasticity and damage after ischemia are key to develop therapeutic interventions. In this application, we propose studies to investigate synaptic damage and plasticity after brain ischemia.